Stark et al (Nature, 278, 471 (1979) showed that the synthetase responsible for making pppA2'pA2'pA (2-5A) from ATP is present in many different cells and that the level of this enzyme increases upon arrest of growth (mammalian cells) or withdrawal of hormones (chick cells). Since 2-5A causes mRNA degradation in virus-infected interferon-treated cells of these species, a more general role for the 2-5A system in regulated mRNA degradation was suspected but could not be tested because the synthetase does not function in the absence of an activator (dsRNA in the case of infected cells). A direct radioimmune assay for 2-5A, sensitive to physiological (nM) concentrations and specific enough for use with crude extracts is now nearly ready. It will be used to correlate the kinetics of appearance of 2-5A in cells with the onset of general mRNA degradation upon arrest of growth induced by contact inhibition, starvation, and inhibitors, with the onset of general and specific mRNA degradation upon withdrawal of hormones from chick oviducts (ovalbumin, conalbumin), from dexamethasone-treated hepatoma cells (tyrosine amino transferase), from thyroxine and corticoid-treated pituitary cells (growth hormone) and with the change in mRNA populations during the development of myoblasts to myotubes in culture. In one or two of these systems, the nature of the activator for 2-5A synthetase will be explored, followed by investigation of the control of activator synthesis. If specific mRNA degradation is observed, the basis of the specificity will be investigated. We also will synthetize and test as antiproliferative agents analogs of 2-5A designed for ease of transport into cells and metabolic stability.